The mesolimbic system plays a critical role both in modulating pain and mediating the response to opiates. This has been discussed in detail under General Description of the Overall Center. This system of dopaminergic neurons that project from the ventral tegmental area (VTA) has been implicated in the reward mechanism of opiates and is a focal point in the process of addiction (Koob and Le Moal, 2001;Nestler, 2004; Volkow et al., 2004;Nestler, 2005;Spanagel and Heilig, 2005). Moreover, a common attribute of drugs of abuse is the release of dopamine in NAc. Adaptations within this system are believed to be a mechanism of addiction. Alterations within the dopaminergic system also have been found to be associated with pain states in both animal and human imaging studies (Borsook and Becerra, 2006;Schweinhardt et al., 2006). Evidence for the important role of striatal D2DR in modulating pain in humans has been reviewed recently by Hagelberg et al. (Hagelberg et al., 2004). This convergence of brain regions and receptor system that impact upon both modulation of pain and the rewarding effects of drugs of abuse suggests the central hypothesis to be tested by this proposal.